PROJECT ABSTRACT Major challenges in the study and treatment of Alzheimer?s Disease (AD) include the pressing need to illuminate the causative molecular mechanisms underlying this disease and to identify robust biomarkers that can predict an individual?s likelihood of developing AD prior to the onset of symptoms. Previous studies have shown an age-related decline in olfactory sensory function in humans. Intriguingly, olfactory dysfunction is also associated with degenerative conditions including AD and in some cases can predict in healthy individuals whether they will later develop AD. The molecular, cellular and anatomic underpinnings of these observations have yet to be fully characterized, however. Working under the scope of the parent grant, in this supplement we plan to use single-cell RNA-sequencing to extend our characterization of olfactory horizontal basal cells (HBCs) ? the deep reserve stem cells of the olfactory epithelium ? and their regenerative capacity to include an analysis during normal aging. We will also use single-cell RNA-sequencing to search for molecular changes associated with early stages of degeneration in a mouse model of AD. Our overall goal is to identify the molecular basis for age-associated decline in olfactory function and understand the association between anosmia and AD. The research proposed in this supplemental application also has the potential to identify early stage molecular biomarkers for AD. Further, by incorporating an analysis of the molecular changes associated with age-related decline in olfactory function we expect to reveal the mechanisms and pathways driving early disease progression itself in AD and other neurodegenerative diseases.